IL-1β enhances vascular smooth muscle cell proliferation and migration via P2Y2 receptor-mediated RAGE expression and HMGB1 release

Vascular smooth muscle cells (VSMCs) are the major cell type in blood vessel walls, and their proliferation and migration play important roles in the development of atherosclerosis. Recently, it has been reported that IL-1β mediates the inflammatory response through the upregulation of the P2Y₂ receptor (P2Y₂R). Thus, we examined the role of P2Y₂R in IL-1β-mediated proliferation and migration of VSMCs and the underlying molecular mechanisms. VSMCs were pretreated with IL-1β for 24 h to upregulate P2Y₂R expression. The cells were then stimulated with UTP or ATP for the indicated times, and cell proliferation and migration and the related signaling pathways were examined. The equipotent P2Y₂R agonists ATP and UTP enhanced proliferation, RAGE expression and HMGB1 secretion in IL-1β-pretreated VSMCs. Additionally, pretreatment with IL-1β enhanced UTP-mediated VSMC migration and MMP-2 release, but these effects were not observed in the P2Y₂R-siRNA- or RAGE-siRNA-transfected VSMCs. Next, the signaling molecules involved in P2Y₂R-mediated cell proliferation and migration were determined. The ERK, AKT, PKC, Rac-1 and ROCK2 pathways were involved in UTP-induced cell proliferation and migration, MMP-2 and HMGB1 secretion and RAGE expression in the IL-1β-pretreated VSMCs. UTP induced the phosphorylation of ERK, AKT and PKC and the translocation of Rac-1 and ROCK2 from cytosol to membrane as well as stress fiber formation, which were markedly increased in the IL-1β-pretreated VSMCs but not in the P2Y₂R-siRNA-transfected VSMCs. These results demonstrate that pro-inflammatory cytokines associated with atherosclerosis, such as IL-1β, can accelerate the process of atherosclerosis through the upregulation of P2Y₂R.     

Microvascular Dysfunction as a Systemic Disease: A Review of the Evidence

Microvascular dysfunction describes a varied set of conditions that includes vessel destruction, abnormal vasoreactivity, in situ thrombosis, and fibrosis, which ultimately results in tissue damage and progressive organ failure. Microvascular dysfunction has a wide array of clinical presentations, ranging from ischemic heart disease to renal failure, stroke, blindness, pulmonary arterial hypertension, and dementia. An intriguing unifying hypothesis suggests that microvascular dysfunction of specific organs is an expression of a systemic illness that worsens with age and is accelerated by vascular risk factors. Studying relationships across a spectrum of microvascular diseases affecting the brain, retina, kidney, lung, and heart may uncover shared pathologic mechanisms that could inform novel treatment strategies. We review the evidence that supports the notion that microvascular dysfunction represents a global pathologic process. Our focus is on studies reporting concomitant microvascular dysfunction of the heart with that of the brain, kidney, retina, and lung.     

The relation between aortic arch branching types and the location of large vessel occlusion in cardioembolic stroke

Cardiac embolism is the leading etiology of ischemic strokes. There are arguments about the left–right propensity of cardioembolic strokes. This study aimed to reveal the relationship between the different aortic arch types and the location of large vessel occlusion (LVO) in cardioembolic stroke. We retrospectively identified all patients with acute ischemic stroke admitted to our comprehensive stroke center who had medium- to high-risk cardioembolic sources according to the TOAST classification. Only those with LVO and available images of the aortic arch were included. Patients were classified into 3 groups according to the aortic arch types: Type I (n = 44), Type II (n = 105), Type III (n = 36). The thrombus was divided into large thrombus or small thrombus based on the location of LVO. Overall, left-sided strokes (50.8%) were almost equal to right-sided (49.2%). There was a growing tendency for the percentage of left-sided infarcts with advancement of the aortic arch types either in the total cases or in the atrial fibrillation cases, with no statistical difference between the 3 aortic arch types. In type III aortic arch, left-sided strokes (69.0%) were twice than right-sided (31%) in large thrombus (P < 0.05), while right-sided strokes (85.7%) were more common than left-sided (14.3%) in small thrombus (P < 0.05). Conversely, in type Ⅰ and II aortic arches, left-sided strokes were more common than right-sided in small thrombus, while right-sided strokes were more common than left-sided in large thrombus (P < 0.05). The left–right propensity of cardioembolic stroke is related to the proximity of clot lodging in different aortic arch types.     

Regadenoson dynamic computed tomography myocardial perfusion using low-dose protocol for evaluation of the ischemic burden. ULYSSES study

BackgroundThe purpose of this study was to assess the feasibility of low-dose dynamic regadenoson computed tomography perfusion (CTP) protocol, and to determine which parameters provide the best diagnostic yield for the presence and burden of ischemia in reference to the magnetic resonance myocardial perfusion imaging (MR MPI).MethodsFifty six patients with ≥1 intermediate (50–90%) coronary artery stenosis on CTA underwent dynamic stress CTP and MR MPI. The distribution of contrast agent in CTP was represented for each myocardial segment as either absolute or indexed: myocardial blood flow (MBF), myocardial blood volume (MBV), perfused capillary blood volume (PCBV), peak value (PV), time to peak (TTP), respectively.ResultsOf 56 patients (25 females, 63.5 ± 8.5y), 15 (27%) were diagnosed with reversible ischemia and 3 (5%) with fixed ischemia on the MR MPI. The median radiation dose for dynamic CTP scan was 352.00 [276.4–496.6] mGy*cm. The optimal cut-off point for the prediction of reversible ischemia on MR MPI for the absolute parameters were: MBF ≤156.49 (AUC=0.899), MBV ≤15.06 (AUC=0.901), PCBV ≤7.90 (AUC=0.880), PV ≤ 88.30 (AUC=0.766), TTP ≥22.58 (AUC=0.595); and for the indexed: indexed MBF ≤0.78 (AUC=0.926), indexed MBV ≤0.81 (AUC=0.924), indexed PCBV ≤0.70 (AUC=0.894); indexed PV ≤ 0.79 (AUC=0.869), indexed TTP ≤0.87 (AUC=0.685). The best parameters for ischemia detection were indexed MBF and indexed MBV, with sensitivities 91% and 89%, specificities 97% and 96%, NPV 99% and 99%, PPV 76% and 69%, and accuracies 96% and 95%, respectively. In per patient analysis, indexed MBF correlated significantly better with the ischemia burden than any of the absolute parameters (p < 0.01 for all comparisons).ConclusionsRegadenoson dynamic CTP using low-dose protocol is feasible while maintaining high diagnostic accuracy. The best diagnostic value may be provided by indexed parameters, of which indexed MBF and indexed MBV may provide best incremental value in identification of the presence and burden of ischemia.